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Preparation method of Bcl-2 family protein inhibitor synthesis intermediate

A protein inhibitor, bcl-2 technology, applied in the field of medicine, can solve the problems of difficult to obtain pure products and purification difficulties, and achieve the effects of easy large-scale production, process route optimization, environmental protection, high efficiency and cost

Inactive Publication Date: 2019-08-27
MEDICILONMPI PRECLINICAL RES SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In this patent document 3, since two fluorines contained in methyl 2,4-difluorobenzoate can participate in the reaction, there are difficulties in purification; the use of N-Boc-piperazine is more difficult to obtain than the use of dichloroethylamine pure product
[0010] Therefore, existing synthetic routes all have drawbacks, and it is urgent to study new synthetic routes.

Method used

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  • Preparation method of Bcl-2 family protein inhibitor synthesis intermediate
  • Preparation method of Bcl-2 family protein inhibitor synthesis intermediate
  • Preparation method of Bcl-2 family protein inhibitor synthesis intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] The reaction scheme is as follows:

[0060]

[0061] 1. Add 7.25g of the compound methyl p-nitrobenzoate and 60ml of tetrahydrofuran into a 250ml three-necked flask, heat to 50°C under stirring, add 36g of sodium sulfide nonahydrate and 50ml of an aqueous solution of 12g of ammonium chloride dropwise, and react after the dropwise addition 2h, TLC monitors that the reaction is completed, and the reaction solution is transferred to a single-necked rotary flask and the solvent is evaporated, and the remaining mixture solution is suction filtered, and the filter cake is washed and dried to obtain 5.45g of product (2), MS (M+H + )=152.17, the product purity is: 80%.

[0062] 2. Take 5.45g of compound (2) from the previous step, and add 30ml of tert-butanol, 7.2g of compound (3) and 7.2g of sodium carbonate to 100ml in sequence. After the feeding is completed, heat the reaction to reflux for 50h, monitor the reaction with TCL, and cool down when the reaction is over. The ...

Embodiment 2

[0066] The reaction scheme is as follows:

[0067]

[0068] 1. Add 7.25g of the compound methyl p-nitrobenzoate and 100ml of methanol into a 250ml three-necked flask, heat it to 50°C under stirring, add 50ml of an aqueous solution of 36g of sodium sulfide nonahydrate and 12g of aluminum chloride dropwise, and react after the dropwise addition 2h, TLC monitors the end of the reaction, transfers the reaction solution into a single-necked rotary flask and evaporates the solvent, the remaining mixture solution is suction filtered, and the filter cake is washed and dried to obtain 6.05g of product (2), MS (M+H + )=152.17, the purity is 90%.

[0069] 2. Take 6.05g of compound (2) from the previous step, add 30ml of tert-butanol, 6.2g of compound (3) and 6.2g of sodium carbonate to 100ml in sequence. After the feeding is completed, heat the reaction to reflux for 50h, monitor the reaction with TCL, after the reaction is completed, cool The reaction solution was diluted with ethyl...

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Abstract

The invention provides a preparation method of a Bcl-2 family protein inhibitor synthesis intermediate. The preparation method comprises the following steps: (a) taking methyl p-nitrobenzoate as a rawmaterial, enabling the material to react with sodium sulfide under the action of chloride to obtain a compound (2); (b) enabling the compound (2) to react with a compound (3) under an alkaline condition to obtain a compound (4); (c) enabling the compound (4) to react with a compound (5) under an alkaline condition to obtain a compound (6); (d) enabling ester ammonolysis reaction of the compound (6) and ammonia under the action of sodium methoxide and ethylene glycol to obtain a compound (1).

Description

technical field [0001] The invention belongs to the field of medicine, in particular, the invention relates to a preparation method of a synthetic intermediate of a Bcl-2 family protein inhibitor. Background technique [0002] Bcl-2 was first discovered in 1986 and expressed by the Bcl-2 gene, which is a proto-oncogene, and the protein expressed is called the Bcl-2 family protein, and the Bcl-2 family protein is the pathway of apoptosis It is an important protein in tumorigenesis and plays a key role in tumorigenesis and metastasis. The Bcl-2 protein family is the core of apoptosis regulation. Bcl-2 protein, as a key factor in the regulation of apoptosis, is crucial to the normal development and homeostasis of cells. Inhibition of anti-apoptotic Bcl-2 family members has been proved to be an effective means of re-inducing apoptosis in cancer cells, and Bcl-2 protein has been widely recognized as a potential target of anti-tumor drugs. Inhibiting the anti-apoptotic effect of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/155C07C227/04C07C229/60
CPCC07C227/04C07D295/155C07C229/60
Inventor 杨泽心陈春麟周南梅
Owner MEDICILONMPI PRECLINICAL RES SHANGHAI